1. Field of the Invention
The present invention relates generally to the fields of chemistry and radionuclide imaging. More particularly, it concerns compositions and methods involving N4 compounds.
2. Description of Related Art
Radionuclide imaging modalities (e.g., Positron Emission Tomography, PET; Single Photon Emission Computed Tomography, SPECT) map the location and concentration of radionuclide-labeled compounds. To improve the diagnosis, prognosis, planning and monitoring of tissue specific disease treatment, characterization of disease tissue is extensively determined by development of more disease specific pharmaceuticals. PET 18F-fluorodeoxyglucose (FDG) has been used to diagnose and evaluate tumors, myocardial infarctions and neurological diseases. Although tumor metabolic imaging using 18F-FDG has been studied in the last two decades, its clinical practice is still limited by the factors such as easy access, availability and isotope cost. In addition, 18F chemistry is complex and requires longer synthesis times (e.g., 18F-FDG, 40-75 min), and it is difficult to produce multiple agents simultaneously. Thus, it would be desirable to develop a simple chelation technique for labeling agents using metallic isotopes for tissue specific targeted radioimaging and radiotherapy.
Improvement of scintigraphic tumor imaging will benefit from the development of more tumor specific radiopharmaceuticals. Due to greater tumor specificity, radiolabeled ligands as well as radiolabeled antibodies have opened a new era in scintigraphic detection of tumors and have undergone extensive preclinical development and evaluation (Mathias et al., 1996, 1997a, 1997b). Radionuclide imaging modalities (e.g., PET, SPECT) are diagnostic cross-sectional imaging techniques that map the location and concentration of radionuclide-labeled radiotracers. Although CT and MRI provide considerable anatomic information about the location and the extent of tumors, these imaging modalities typically cannot adequately differentiate invasive lesions from edema, radiation necrosis, grading, or gliosis. PET and SPECT can be used to localize and characterize tumors by measuring metabolic activity. Thus, methods that allow for more specific imaging of tumors is desirable.
One approach for producing novel compounds for imaging has involved the use of ethylenedicysteine (EC) derivatives, which are distinct from the compositions of the present invention. Several compounds have been labeled with 99mTc using nitrogen and sulfur chelates (Blondeau et al., 1967; Davison et al., 1980). Bis-aminoethanethiol tetradentate ligands, also called diaminodithiol compounds, are known to form very stable Tc(V)O complexes on the basis of efficient binding of the oxotechnetium group to two thiol sulfur and two amine nitrogen atoms. Radiometal complexes of 2-pyrrolthiones labeled with 99mTc have been developed for use as radiopharmaceuticals for imaging and therapy (WO 0180906A2). 99mTc-L,L-ethylenedicysteine (99mTc-EC) is a recent and successful example of N2S2 chelates. EC can be labeled with 99mTc easily and efficiently with high radiochemical purity and stability, and is excreted through the kidney by active tubular transport (Surma et al., 1994; Van Nerom et al., 1990, 1993; Verbruggen et al., 1990, 1992). Furthermore, 99mTc chelated with ethylenedicysteine (EC) and conjugated with a variety of ligands has been developed for use as an imaging agent for tissue-specific diseases, as a prognostic tool, and as a tool to deliver therapeutics to specific sites within a mammalian body (WO 0191807A2, AU 0175210A5). 99mTc-EC-chelates have been developed for renal imaging and examination of renal function (U.S. Pat. Nos. 5,986,074 and 5,955,053). A method of preparing 99mTc-EC complexes and a kit for performing said method have also been developed (U.S. Pat. No. 5,268,163 and WO 9116076A1). U.S. Pat. No. 6,692,724 discloses ethylenedicysteine drug conjugates and is incorporated by reference herein in its entirety.